Bihormonal Artificial Pancreas: Combining Insulin and Glucagon

What Is a Bihormonal Artificial Pancreas?

The standard artificial pancreas — used by tens of thousands of people with Type 1 diabetes today — works by automatically delivering insulin based on continuous glucose monitor (CGM) readings. It's a remarkable advance. But insulin alone has a fundamental limitation: it can only lower blood sugar. It cannot raise it.

Your healthy pancreas uses two hormones to manage blood glucose: insulin to bring it down, and glucagon to bring it up when levels drop too low. A bihormonal artificial pancreas (also called a dual-hormone closed-loop system) mimics this natural balance by delivering both hormones — giving the system a way to actively rescue falling glucose levels rather than simply cutting off insulin and waiting.

The Scientific Case for Adding Glucagon

Hypoglycemia — dangerously low blood sugar — remains one of the most feared complications of insulin therapy. Even advanced single-hormone closed-loop systems like the Medtronic MiniMed 780G and Tandem Control-IQ can reduce but not eliminate hypoglycemia, particularly during exercise, sleep, and unpredictable activity.

The logic of adding glucagon is straightforward: when the algorithm predicts or detects a glucose drop, it can deliver a small "mini-dose" of glucagon to stimulate the liver to release stored glucose — a faster, more physiological rescue than relying on carbohydrate intake or simply suspending insulin.

Research published in The Lancet Diabetes & Endocrinology and the New England Journal of Medicine has demonstrated that bihormonal systems meaningfully reduce time in hypoglycemia compared to insulin-only closed-loop systems, particularly during physical activity and overnight periods.

Key Clinical Trials and Real-World Evidence

The most extensively studied bihormonal system is the iLet Bionic Pancreas, developed by Beta Bionics. The pivotal iLet Pivotal Trial — a large, randomized multicenter study — demonstrated that the insulin-only version of iLet significantly improved time-in-range compared to standard-of-care. Beta Bionics received FDA approval for the insulin-only iLet in 2023, and the company has continued developing the glucagon-enabled dual-hormone version.

The dual-hormone iLet uses dasiglucagon, a stable liquid glucagon analog developed by Zealand Pharma, which solved a critical practical problem: native glucagon is unstable in liquid form and degrades within hours, making it impractical for pump delivery. Dasiglucagon remains stable at room temperature for days, enabling real-world bihormonal pump use.

Beta Bionics and Zealand Pharma have conducted Phase 2 clinical studies of the dasiglucagon-enabled iLet, with results showing statistically significant reductions in hypoglycemia compared to the insulin-only configuration — without meaningfully increasing hyperglycemia. Their Phase 3 program is underway as of 2025.

Separately, Inreda Diabetic, a Dutch company, has developed its own bihormonal system using native glucagon, which has been studied in European trials. Results published from their work showed strong hypoglycemia reduction but highlighted the ongoing stability challenges with native glucagon formulations.

Academic research groups — including teams at Massachusetts General Hospital and Oregon Health & Science University — have published multiple studies confirming that bihormonal systems outperform insulin-only systems specifically during exercise, a scenario where hypoglycemia risk is highest and hardest to manage algorithmically.

What the Challenges Are

Bihormonal systems are more complex than insulin-only devices — and complexity brings challenges. Key issues include:

• Glucagon side effects: Even mini-doses can cause nausea in some patients, particularly at higher cumulative daily doses.
• Cost and cartridge management: Carrying two hormone cartridges increases device bulk and expense.
• Regulatory pathway: The FDA must evaluate not just the device but the drug-device combination, which adds approval complexity.
• Long-term glucagon effects: Daily low-dose glucagon exposure over years has not been fully studied — liver glycogen depletion and metabolic effects require longer follow-up.

Current Status (2025)

As of 2025, no bihormonal artificial pancreas has received FDA approval for commercial use in the United States. The Beta Bionics / Zealand Pharma Phase 3 program is the most advanced in the U.S. pipeline. European regulatory pathways are being pursued in parallel. Patients interested in participating in active trials can search ClinicalTrials.gov using the terms "bihormonal closed loop" or "dasiglucagon artificial pancreas" to find enrolling studies. Meanwhile, insulin-only closed-loop systems — available now and discussed in detail at mdsdiabetes.com — remain the current standard of care for automated insulin delivery.

Timeline: When Might This Be Available?

Realistically, the first FDA-approved bihormonal system is unlikely before 2027 at the earliest, assuming Phase 3 results are positive and the regulatory review proceeds without major obstacles. European availability may come slightly earlier. This is not a technology patients should expect imminently — but it is one of the most credible near-term advances in Type 1 diabetes management.

What This Means for Patients

If you live with Type 1 diabetes and hypoglycemia unawareness, exercise-induced lows, or persistent overnight hypoglycemia despite using a current closed-loop system, bihormonal technology is specifically designed to address your hardest-to-solve problem. It won't replace good diabetes management — but it may add a meaningful safety layer that today's best technology still can't fully provide. Talk to your endocrinologist about whether you're a candidate for current trials, and keep a close watch on Beta Bionics' Phase 3 results expected in the next 12–24 months.